Patients with severe beta thalassemia or sickle cell anemia would benefit significantly if HbF production could be consistently augmented. The imbalance of globin synthesis characteristic of thalassemia could be partially corrected by increased gamma globin synthesis. Reduction of intracellular HbS concentration by replacement with HbF reduces the polymerization potential of intracellular sickle hemoglobin, decreasing the sickling "propensity" of red cells from such individuals. Several classes of substances stimulate HbF synthesis including cytotoxic agents (e.g. hydroxyurea), hematopoietic growth factors (erythropoietin) and agents that modify DNA or chromatin structure (e.g. 5Azacytidine or sodium butyrate, respectively). The combination of hydroxyurea and sodium butyrate has been tested in the rhesus model. Both "low" and "high" responders to hydroxyurea show a substantial increment in F-reticulocyte production when sodium butyrate infusions are given to animals already receiving oral hydroxyurea. Our prior studies in the rhesus model had shown that erythropoietin given cyclically for three days following four days of oral hydroxyurea caused a substantial increase in F-reticulocyte production. These results have proved predictive for human trials in that four patients treated with this regiment have shown significant increments in HbF when erythropoietin was given in addition to oral hydroxyurea. Two patients with severe beta thalassemia continue to receive monthly infusions of 5-Azacytidine with partial correction of anemia and elimination of transfusion requirements.